The Zucker diabetic fatty rat is a well accepted model of human obesity and NIDDM. Animals inheriting a defect in the leptin receptor (fa/fa) develop early obesity insulin resistance and in males, NIDDM due to their leptin resistance. We have demonstrated that spectral analysis of whole body fat content detects the pre-obese (fa/fa) genotype before gross obesity and other metabolic derangements develop. In addition, this analysis provides a measure of lean body mass using our previous validated technique of fat and whole body water detection. We are finding that this animal model has a co-existent defect in lean body mass accumulation. Paradoxically in a second model using i.c.v. leptin infusion into normal rats, we are observing accelerated lean body mass loss in addition to augmented fat oxidation mediated by the central effects of leptin. Hyperinsulinemic glucose clamp studies in these two animal models suggest that there is strong correlation between intramyocellular triglyceride content and insulin sensitivity. We have been able to specifically monitor intramyocellular lipids through the use of proton spectroscopy and have previously validated its use in dogs and rabbits using the 1.5T clinical MR system at the Rogers MR Center. Studies are currently in progress to better understand the relationship between amounts and types of dietary fats, leptin, leptin resistance, intra-myocellular triglyceride stores and the development of insulin resistance and impaired insulin secretory response. (Service 5) REPORT PERIOD: (09/01/97-08/31/98)